Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
  • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays

Definitions

• the present invention relates to a means of aleviating pain and, more particularly, to a method of, and formulations for, introducing alkoxybenamides into the systemic circulation system.
• alkoxybenzamides can be introduced into the systemic circulation system through mucous membranes when the membrane is contiguous to a large supply of blood to provide a route of administration comparable to that of the parenteral route of administration.
• R is an alkyl group having 1 to 5 carbon atoms.
• ortho-ethoxybenzamide ortho-ethoxybenzamide (oethoxybenzamide or OEB) represented by the formula:
• OEB has been chosen as the representative of the alkoxybenzamides because it is commercially available and representative of the class defined hereinbefore.
• the drug can be administered at any time and no special need such as water is required.
• the analgesic action of the drug is much greater than that of salicylates and phenactin-like drugs and does not cause gastro-intestinal irritation.
• the experimental analgesic activity of the drug is comparable to certain narcotic drugs, e.g., codeine, but still is not a narcotic and does not possess the toxic side eflects of narcotics.
• the drug can be administered to patients unable to take analgesics per se.
• the most readily accessible mucous membranes contiguous to large supplies of blood are the mucous membrane of the oral or buccal cavity, that of the lungs, the mucous membrane of the rectum and that of the vagina.
• the present method of the formulations for, administrating alkoxybenzamides provides introduction of the benzamide directly into the arterial circulation without involvement of the upper gastrointestinal tract, intravenous or other parenteral routes of administration.
• the advantage of the present method is that passage of the drug through the liver is prevented prior to arrival of the drug at the side of action. Degradation of the drug readily occurs at this site, i.e., the liver, therefore results in a reduction of the available active molecules.
• the present method of contacting a mucous membrane contiguous to the systemic circulatory system assures a greater adsorption of the intact molecule of the drug into the arterial, vascular network and therefore a larger retention of the intact molecules of the drug for delivery to sites within the central nervous system resulting in the induction of analgesia.
• a mucous membrane contiguous thereto such as the lungs
• either a solution of the alkoxybenzamide suitable for use with a nebulizer or an aerosol formulation is used for introduction through the oral mucous into the systemic circulatory system
• a sub-lingual tablet or lozenge can be used.
• For introduction into the systemic circulatory system through the mucous membrane of the vagina or the rectum supporitories or tablets can be used.
• Solvent Maximum concentration, percent Water (cold) 0.05 Water (hot, about F.) 0.10 Ethanol (hot) 5.00 Propylene glycol (hot) 2.00
• the solvent for the ortho-ethoxybenzarnide in addition to being a solvent for the drug must possess these other characteristics (1) it must be a solvent for lipoids and nonpolar materials; (2) it must be non-toxic; and (3) it must be well tolerated by the organism.
• the denominator is the number of test animals; the numerator 1s the number of test animals reacting.
• HOT PLATE REFLEX This reflex is an extension of the flexor withdrawal response, e.g., the occurrence of a painful stimulus results 6 in the animals attempt to escape.
• the stimulus employed is a thermal one. This standard procedure originally was devised by Woolfe and MacDonald and reported in].
• Orthoethoxybenzamide supplied by four manufacturers was tested.
• the OEB was administered by the low pressure aerosol inhalation route (nebulizer) with the results as indicated hereinafter.
• the test mice were exposed for five minutes employing a 0.4% to 0.8% solution as indicated.
• Aerosol inhalation employing nebulizor
• the skin twitch reflex in rabbits is based essentially upon the principle that the latent response of the skin to twitch, when an electrical stimulus is applied, is a function of the animals sensitivity threshold.
• the stimulus is delivered through bipolar platinum electrodes spaced one centimeter apart to the dorsal skin of the animal.
• the power source is a Thomas Square Wave Stimulator which delivers a direct current square wave pulse at 120 c.p.s. with 0.3 msec. pulse delay.
• Each animal is prepared by cleanly shaving the hair from the dorsolumbar area with an electric clipper. Four concentric sites one centimeter in diameter are demarcated with indelible ink; two on either side of the middle.
• the response time is recorded by the observer employing a stop watch.
• the alkoxybenzamide in this instance orthoethoxybenzamide, was administered by placing a mask over the rabbits face, introducing the OEB into the mask from a nebulizer, and allowing the rabbit to inhale the drug for a period of five minutes.
• the assigned dose is an approximation.
• Table V The results are set forth in Table V.
• Electrode site No. Minutes after 1 2 3 4 adminis- Response time 0 EB rug/kg Volts tration seconds 999 992-99 2"??? FNNE"? 0201000 @0000 numb moemoon OOOnhNO 'oooooonc oooemao Electrode site No. Minutes after 1 2 3 4 adminis- Response time,
• a propellant or propellants is used in the high pressure aerosol inhalation method of administering alkoxybenzamides (high pressure relative to the pressure of a nebulizer).
• the propellant(s) and the solvent(s) preferably are mutually soluble.
• the propellant(s) must be non-toxic, must evaporate so rapidly as to produce a relatively dry spray with the result that only dry material, i.e., substantially only the alkoxybenzamide reaches the transport sites, i.e., the mocous membranes of the mouth, trachea, bronchia, and lungs including the alveolar sac.
• the propellant(s) preferably is the liquefied normally gaseous low molecular weight halogenated hydrocarbons, such as halogenated ethane, methane, and/or mixtures thereof.
• halogenated hydrocarbons known in the art as the Freons and Genetrons and the like have been found to be particularly suitable.
• Specific examples of such propellants are dichlorodifiuoromethane (Freon 12), dichlorotetrafiuoroethane (Freon 114), trichloromonofluoroethane (Freon 11), trifluoroethylchloride and monochlorodifluoromethane (Freon 22).
• any fluorinated hydrocarbon propellant or combination of fluorinated hydrocarbon propellants or compressed gas, e.g., nitrous oxide, carbon dioxide, compatible with a suitable co-solevnt system and approved for food and/or drug application can be used.
• the solution of the particular propellant-solvent should be integrated with the type of container and the particular vapor pressure desired.
• compositions Illustrative of the variation in solvents and in propellant composition which have been tested are the following compositions:
• Solvent A percent Wt 40. 0 40. 0 40.0 35. 0 40. 0 00. 0 80. 0 08. 0 00. 0 08.0
• Solvent B percent wt.. 40. 0 40. 0 40.0 35. 0 40.0 0. 0 10.0 12.0 10.0 12.0
• Solvent C percent wt 8.0 8. 0 10. 0 10. 0
• Propellant-solvent A is trichloromonofluorometnane.
• Propellant-solvent B is dichlorodifluoromethane.
• Propellant-solvent C is trifluoroethyl chloride.
• Sample number 4 tends to separate into two distinct layers. However, it is easily dispersed with shaking and operative if shaken before using.
• Sample number 5 is satisfactory though hazy.
• Sample numbers 7 and 8 are satisfactory although each has a tendency to settle into two layers but each is readily dispersed with shaking.
• the areosol compositions samples 1 through 10 were dispensed through Emson M- PFG metering valves discharging 50 milligrams of the aerosol composition per actuation.
• the calculated dosages for the four most satisfactory combinations of ingredients are as follows:
• the concentration of the drug is limited by the concentration which can be dispensed through a specific valve and by its solubility in the propellant-solvent system.
• concentration which can be dispensed through a specific valve and by its solubility in the propellant-solvent system.
• concentration for discharge through Emson M-20 PFG valves the'limiting concentration for ortho-ethoxybenzamide is about 2%.
• the aerosol composition comprises about 2% by weight of ortho-ethoxybenzamide, propellant-solvent 70 to 98% by weight, and auxiliary solvent or co-solvent the balance to make 100%.
• orthoethoxybenzamide given by aerosol inhalation to mice will adequately protect them from writhing induced by an intra-peritoneal injection of para-phenylquinone and also significantly elevate their thermic skin tolerance time threshold.
• dosages of the drug in which the non-Freon propellant system was employed equivalent dosages in a solvent system such as exemplified by the propellant solvent systems of Samples No. 9 and 10 in Table VI were found to produce effects which were comparable.
• the formulation of orthoethoxybenzamide in a solvent system such as described hereinbefore represents a means by which a relatively poorly soluble substance can be dissolved in the propellant solvent system and administered via the aerosol inhalation route.
• 1O laxants e.g., maprobamate, (Chordiazepoxide Hcl).
• the aerosol analgesic composition of the present invention provides rapid onset of action with minimal dosage, reduced side effects, and a convenient and esthetically more attractive form of medication.
• the efficacy of the route of administration provided by the sublingual tablet has been demonstrated and may be related to the rapid absorption and transportation of the drug to its locus of action before going to the liver where it is chemically altered.
• the intactness of the drug molecule and its delivery to the site of action are directly related to the route of administration.
• this route of administration because of its augmenting action on potency, allows for a reduced amount to be employed for therapeutic value. Therefore, this route of administration reduces the possibility of side effects.
• the advantages of the use of a sublingual tablet for the admininstration of orthoethoxybenzamide are (1) rapid onset of drug activity; (2) more potent and prolonged actions from the drug because it is not chemically altered by the liver before arriving at the site of the action; and (3) a reduced amount is required since oral trans-mucosal absorption is complete within minutes in contrast to gastro-intestinal absorption in which about fifty percent of the drug is absorbed within six hours.
• the sublingual administration of orthoethoxybenzamide has the following advantages over the oral method of administration previously recommended; (1) the drug can be administered at any time without any need for assisting means such as potable water to wash the drug from the mouth, (2) the action of the orthoethoxybenzamide in smaller doses is much greater than that of orally administered salicylates and phenacetin-like drugs and does not cause gastrointestinal irritation; (3) the analgesic effectiveness of the drug is comparable to that of certain narcotic drugs, e.g., codeine, but without the hazards of the narcotic side effects, (4) the administration of orthoethoxybenzamide by this route is especially beneficial in relieving pain which is refractive to salicylates and other non-narcotic agents.
• formulations 4, 5 and 6 contain- It is within the purview of the present invention to ing no PVP exhibit greater disintegrating capabilities incorporate other analgesic drugs, e.g., acetylsalicyclic acid; anti-histamines, fig chloropheniramine, Benadryl; [Z-(diphenylmethoxy) N,N dimethylethylamine hydrochloride]; bronchodilators, e.g., isoproterenol, ephedrine; sedatives, e.g., pentobarbital; centrally acting muscle rethan the formulation 1 in which there is PVP.
• formulation 6 represents a more refined and acceptable dosage form.
• Milligrams per tablet can be made as required.
• therapeutic Cyclamate Sodium, N.F. Zero to about 20.0. amounts of steroids, antihistamines, broncho-dilators, Saccharine Sodium, U.S.P. Zero to about 5.0.
• Flavors Zero to about 10.0. may be absorbed sublingually or via the gastro-intesti- Starch, micro Zero to about 15.0. nal tract if delayed and additional absorption is desired: Urea, N.F. Zero to about 10.0.
• steroids dexamethane sulfate
• antihistamines chlorophen- Incorporation of other analgesic durgs steroids anti lramme .maleate
• bronchodllator lsoproterepol pamsym' histamines broncho-dilators, parasympatliolytic aiitituspatholytlc agent atropme sulfate
• antltu repet sive sedative and/or muscle relaxants in an br all of tromethorphan HBr are examples of drugs that may be the formulations set forth herein can be s ⁇ ?
• a densifier Such as PVP an contiguous thereto as illustrated he rembefor e or through cipient such as lactose siiccrose and a die lubricant such th?
• Orthoethoxybenzamide About 10 to about 100. 27 using commercially available orthoethoxybenzamide, for- Polyvinylpyrrolidone Zero to about 2.5. mulations in the ranges set forth in Table VIII are use- Starch, arrowroot About 7 to about 14.0. ful.
• Polyethylene glycol 1000 (watersoluble polyethylene glycol polymer,mol. ⁇ vt.950to 1,050) 35.00-90.00 1. 00-40. 00
• Polyethylene glycol 4000 (watersoluble polyethylene glycolpolymer, mol. wt. 3,000 to 3,700) 1. 00-15. 00 1, 00-70. 00
• Glycerol monostearate 165 (acidstable, sell-emulsifying glycerol monostearate) 1. 00-30. 00
• Absolute ethanol-Ethanol USP can be used.
• Propylene glycol-Absolute ethanol or Ethanol USP can be used in whole or in part.
• Ethanal USP can be used in whole or in par Dilluorodiehloromethane-Diiluoromonochloromethane, octofluoroeyclobutane can be used in whole or in part.
• mice0starel1Arro ⁇ vroot starch, potato starch, purified talc can be used in whole or in part.
• Magnesium stearatcSodium stcarate, tale, stearic acid can be used in whole or in part.
• UreaSulka Floc purified cellulose
• aminoacctic acid aminoacctic acid
• earboxymethylcellulose acid can be used in whole or in part.
• Cyclamate sodiu1nHexamic acid, sucrose, mannitol can be used in whole or in part.
• saccharine sodium-Saccharine calcium can be used in whole or in part.
• Sorbitol solution-Glycerin can be used in whole or in part.
• Polyethylene glycol 1000-Theobroma oil, polyethylene glycol 1540, polyethylene glycol 6000, glycerine, gelatin can be used in whole or in part.
• Mineral oil0live oil, glycerin, cottonseed oil can be used in whole or in part.
• Glycerol monostearate -Sodium Oleate, trlethauolamine oleate can be used in Whole or in part.
• oral ingestion would be indicative that sublingually the drug is self limiting.
• a method of administering ortho-ethoxybenzamide which comprises introducing into the oral cavity to con- 40 tact a mucous membrane contiguous to the systemic circulatory system a composition comprising a therapeutically effect amount of ortho-ethoxybenzamide in a nontoxic pharmaceutical carrier adapted to provide rapid and substantially complete absorption of said orthoethoxybenzamide when in contact with said mucous membrane, said composition being in the form of a sublingual tablet.
• said tablet comprises about 0.10 to about 99.0% by weight of orthoethoxybenzamide and the balance, to make 100% by weight, of said carrier.

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• Health & Medical Sciences (AREA)
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• General Health & Medical Sciences (AREA)
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• Bioinformatics & Cheminformatics (AREA)
• Life Sciences & Earth Sciences (AREA)
• Public Health (AREA)
• Pulmonology (AREA)
• Otolaryngology (AREA)
• Nutrition Science (AREA)
• Physiology (AREA)
• Medicinal Preparation (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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Cited By (6)

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• 1967
  • 1967-02-20 US US617058A patent/US3560625A/en not_active Expired - Lifetime
  • 1967-11-18 GR GR670136834A patent/GR36834B/el unknown
• 1968
  • 1968-01-11 ES ES349148A patent/ES349148A1/es not_active Expired
  • 1968-02-07 DE DE19681667872 patent/DE1667872A1/de active Pending
  • 1968-02-15 GB GB7524/68A patent/GB1209849A/en not_active Expired
  • 1968-02-19 AT AT152468A patent/AT277448B/de not_active IP Right Cessation
  • 1968-02-19 FR FR140313A patent/FR7355M/fr not_active Expired
  • 1968-02-19 IE IE206/68A patent/IE32432B1/xx unknown
  • 1968-02-20 BE BE711048D patent/BE711048A/xx unknown
  • 1968-02-20 NL NL6802422A patent/NL6802422A/xx unknown

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